Glucose is the most important energy source for cell growth; therefore, a fast-growing cancer cell requires more glucose than a normal cell. One of the biochemical markers in respects to tumor malignancy is the enhanced glycolysis due to the overexpression of glucose transporters (GLUTs) and the increased activity of hexokinases (phosphorylation catalytic enzyme of hexose) in tumors [M. Zhang, Z. Zhang, D. Blessington, H. Li, T. M. Busch, V. Madrak, J. Miles, B. Chance, J. D. Glickson, G Zheng, Bioconjugate Chem. 2003, 14, 709-714].
The in vitro and in vivo assessment of glucose utilization has been of considerable interest to scientific communities, especially those in the biological and biomedical fields. One of the successful applications of this assessment is tumor diagnosis by positron emission tomography (PET) using a glucose probe of 18F 2-fluoro-2-deoxyglucose (18FDG) where 18F (fluoride) is used as an isotope that emits a positron [P. Som, H. L. Atkins, D. Bandoypadhyay, J. S. Fowler, R. R. MacGregor, K. Matsui, Z. H. Oster, D. F. Sacker, C. Y. Shiue, H. Turner, C. N. Wan, A. P. Wolf, S. V. Zabinski, J. Nud Med. 1980, 21, 670-675; H. Yorimitsu, Y. Murakami, H. Takamatsu, S. Nishimura, E. Nakamura, Angew. Chem. Int. Ed. 2005, 44, 2708-2711]. PET with 18FDG is a molecular imaging modality that monitors metabolic perturbation in tumor cells and allows the imaging of the exact positions of tumors in the human body; therefore, it is widely applied in the diagnosis of various tumors [P. S. Conti, D. L. Lilien, K. Hawley, J. Keppler, S. T. Grafton, J. R. Bading, Nucl, Med, Biol. 1996, 23, 717-735; J. Czernin, M. E. Phelps, Annu. Rev. Med. 2002, 53, 89-112.].
A fluorescent 2-deoxyglucose analog, i.e., 2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino]-2-deoxy-D-glucose (2-NBDG), was developed and extensively studied, primarily by Yoshioka et al. [K. Yoshioka, H. Takahashi, T. Homma, M. Saito, K. B. Oh, Y. Nemoto, H. Matsuoka, Biochim. Biophys. Acta. 1996, 1289, 5-9.]. 2-NBDG has been widely applied in various studies, especially for tumor imaging and examination of GLUT-related cell metabolism [K. Yoshioka, H. Takahashi, T. Homma, M. Saito, K. B. Oh, Y. Nemoto, H. Matsuoka, Biochim. Biophys. Acta. 1996, 1289, 5-9; K. Yoshioka, M. Saito, K. B. Oh, Y. Nemoto, H. Matsuoka, M. Natsume, H. Abe, Biosci. Biotech. Biochem. 1996, 60, 1899-1901; A. Natarajan, F. Srienc, J. Microbiol. Methods. 2000, 42, 87-96]. In addition, some 2-deoxyglucose analogs have been reported [Z. Cheng, J. Levi, Z. Xiong, O. Gheysens, S. Keren, X. Chem, S. S. Gambhir, Bioconjugate Chem. 2006, 17, 662-669; Z. Zhang, H. Li, Q. Liu, L. Zhou, M. Zhang, Q. Luo, J. Glickson, B. Chance, G Zheng, Biosensors and Bioelectonics. 2004, 20, 643-650; Y. Ye, S. Bloch, S. Achilefu, J. Am. Chem. Soc, 2004, 126, 7740-7741].
However, these analogs are all N-2-glycosylated analogs, and are disadvantageous in that a difference according to the type of α and β anomers of glucose cannot be confirmed, and that while D-glucose is an important energy source the cellular uptake of the analogs occurs only in a D-glucose-free medium, thus, it cannot be applied to a cell test in practice. Therefore, known 2-NBDG or N-2-glycosylated analogs cannot be used in the case of when the medication of an anti-cancer medicine, or obesity-related studies or diseases (e.g. diabetes) is screened.
Accordingly, the present inventors designed and synthesized novel glucose analogs in which a fluorescent dye is labeled by O-1-glycosylation unlike the known N-2-glycosylated glucose analogs.